. 2020 Feb 3;11(1):667.

doi: 10.1038/s41467-019-14279-8.

Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study

Eric M Reiman^{1

2

3

4}, Joseph F Arboleda-Velasquez⁵, Yakeel T Quiroz⁶, Matthew J Huentelman⁷, Thomas G Beach⁸, Richard J Caselli⁹, Yinghua Chen⁸, Yi Su⁸, Amanda J Myers¹⁰, John Hardy¹¹, Jean Paul Vonsattel¹², Steven G Younkin¹³, David A Bennett¹⁴, Philip L De Jager¹⁵, Eric B Larson¹⁶, Paul K Crane¹⁷, C Dirk Keene¹⁸, M Ilyas Kamboh¹⁹, Julia K Kofler²⁰, Linda Duque²¹, John R Gilbert²², Harry E Gwirtsman²³, Joseph D Buxbaum²⁴, Dennis W Dickson²⁵, Matthew P Frosch²⁶, Bernardino F Ghetti²⁷, Kathryn L Lunetta²⁸, Li-San Wang²⁹, Bradley T Hyman³⁰, Walter A Kukull³¹, Tatiana Foroud³², Jonathan L Haines³³, Richard P Mayeux³⁴, Margaret A Pericak-Vance²², Julie A Schneider¹⁴, John Q Trojanowski²⁹, Lindsay A Farrer^{28

35

36

37}, Gerard D Schellenberg²⁹, Gary W Beecham²², Thomas J Montine³⁸, Gyungah R Jun³⁵; Alzheimer’s Disease Genetics Consortium

Collaborators, Affiliations

Collaborators

Alzheimer’s Disease Genetics Consortium:
Erin Abner, Perrie M Adams, Marilyn S Albert, Roger L Albin, Liana G Apostolova, Steven E Arnold, Sanjay Asthana, Craig S Atwood, Clinton T Baldwin, Robert C Barber, Lisa L Barnes, Sandra Barral, James T Becker, Duane Beekly, Eileen H Bigio, Thomas D Bird, Deborah Blacker, Bradley F Boeve, James D Bowen, Adam Boxer, James R Burke, Jeffrey M Burns, Nigel J Cairns, Laura B Cantwell, Chuanhai Cao, Chris S Carlson, Cynthia M Carlsson, Regina M Carney, Minerva M Carrasquillo, Helena C Chui, David H Cribbs, Elizabeth A Crocco, Carlos Cruchaga, Charles DeCarli, Malcolm Dick, Rachelle S Doody, Ranjan Duara, Nilufer Ertekin-Taner, Denis A Evans, Kelley M Faber, Thomas J Fairchild, Kenneth B Fallon, David W Fardo, Martin R Farlow, Steven Ferris, Douglas R Galasko, Marla Gearing, Daniel H Geschwind, Valentina Ghisays, Alison M Goate, Neill R Graff-Radford, Robert C Green, John H Growdon, Hakon Hakonarson, Ronald L Hamilton, Kara L Hamilton-Nelson, Lindy E Harrell, Lawrence S Honig, Ryan M Huebinger, Christine M Hulette, Gail P Jarvik, Lee-Way Jin, Anna Karydas, Mindy J Katz, John S K Kauwe, Jeffrey A Kaye, Ronald Kim, Neil W Kowall, Joel H Kramer, Brian W Kunkle, Amanda P Kuzma, Frank M LaFerla, James J Lah, Yuk Ye Leung, James B Leverenz, Allan I Levey, Ge Li, Andrew P Lieberman, Richard B Lipton, Oscar L Lopez, Constantine G Lyketsos, John Malamon, Daniel C Marson, Eden R Martin, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Wayne C McCormick, Susan M McCurry, Andrew N McDavid, Stefan McDonough, Ann C McKee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, John C Morris, Shubhabrata Mukherjee, Adam C Naj, Sid O'Bryant, John M Olichney, Joseph E Parisi, Henry L Paulson, Elaine Peskind, Ronald C Petersen, Aimee Pierce, Wayne W Poon, Huntington Potter, Liming Qu, Joseph F Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Joan S Reisch, Christiane Reitz, John M Ringman, Erik D Roberson, Ekaterina Rogaeva, Howard J Rosen, Roger N Rosenberg, Donald R Royall, Mark A Sager, Mary Sano, Andrew J Saykin, Lon S Schneider, William W Seeley, Amanda G Smith, Joshua A Sonnen, Salvatore Spina, Peter St George-Hyslop, Robert A Stern, Russell H Swerdlow, Rudolph E Tanzi, Juan C Troncoso, Debby W Tsuang, Otto Valladares, Vivianna M Van Deerlin, Linda J Van Eldik, Badri N Vardarajan, Harry V Vinters, Sandra Weintraub, Kathleen A Welsh-Bohmer, Kirk C Wilhelmsen, Jennifer Williamson, Thomas S Wingo, Randall L Woltjer, Clinton B Wright, Chuang-Kuo Wu, Chang-En Yu, Lei Yu, Yi Zhao

Affiliations

¹ Banner Alzheimer's Institute and Arizona Alzheimer's Consortium, 901 E Willetta Street, Phoenix, AZ, 85006, USA. eric.reiman@bannerhealth.com.
² University of Arizona, 714 E Van Buren Street, Phoenix, AZ, 85006, USA. eric.reiman@bannerhealth.com.
³ Arizona State University, 522 N Central Avenue, Phoenix, AZ, 85004, USA. eric.reiman@bannerhealth.com.
⁴ Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, 445 N Fifth Street, Phoenix, AZ, 85004, USA. eric.reiman@bannerhealth.com.
⁵ Schepens Eye Research Institute of Mass Eye and Ear and the Department of Ophthalmology at Harvard Medical School, 20 Staniford Street, Boston, MA, 02114, USA.
⁶ Departments of Psychiatry and Neurology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
⁷ Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, 445 N Fifth Street, Phoenix, AZ, 85004, USA.
⁸ Banner Alzheimer's Institute and Arizona Alzheimer's Consortium, 901 E Willetta Street, Phoenix, AZ, 85006, USA.
⁹ Mayo Clinic, 13400 E Shea Boulevard, Scottsdale, AZ, 85259, USA.
¹⁰ Department of Psychiatry and Behavioral Science, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL, 33136, USA.
¹¹ Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
¹² New York Brain Bank and Department of Pathology, New York-Presbyterian Hospital at Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
¹³ Departments of Neuroscience and Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
¹⁴ Departments of Neurological Sciences and Pathology (Neuropathology), and Rush Alzheimer's Disease Center, Rush University Medical Center, 1725 W Harrison Street, Chicago, IL, 60612, USA.
¹⁵ Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, 710 West 168th Street, New York, NY, 10032, USA.
¹⁶ Kaiser Permanente Washington Health Research Institute, 1730 Minor Avenue, Seattle, WA, 98101, USA.
¹⁷ Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98198, USA.
¹⁸ Department of Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98198, USA.
¹⁹ Department of Human Genetics, Alzheimer's Disease Research Center, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.
²⁰ Department of Pathology (Neuropathology), University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.
²¹ Department of Neurology, University of Miami, 1120 NW 14th Street, Miami, FL, 33136, USA.
²² John P. Hussman Institute for Human Genomics, Department of Human Genetics, and Dr. John T. Macdonald Foundation, University of Miami, 1501 NW 10th Avenue, Miami, FL, 33136, USA.
²³ Department of Psychiatry, Vanderbilt University, 1601 23rd Avenue South, Nashville, TN, 37212, USA.
²⁴ Departments of Psychiatry, Neuroscience and Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1468 Madison Avenue, New York, NY, 10029, USA.
²⁵ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
²⁶ C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA, 02129, USA.
²⁷ Department of Pathology and Laboratory Medicine, Indiana University, 340 West 10th Street, Indianapolis, IN, 46202, USA.
²⁸ Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA, 02118, USA.
²⁹ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, PA, 19104, USA.
³⁰ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
³¹ Department of Epidemiology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
³² Department of Medical and Molecular Genetics, Indiana University, 410W 10th Street, Indianapolis, IN, 46202, USA.
³³ Institute for Computational Biology and Department of Population and Quantitative Health Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
³⁴ Taub Institute on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center Department of Neurology, Columbia University, 710 West 168th Street, New York, NY, 10032, USA.
³⁵ Biomedical Genetics Section, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
³⁶ Department of Neurology, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
³⁷ Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, Boston, MA, 02118, USA.
³⁸ Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305, USA.

PMID: 32015339
PMCID: PMC6997393
DOI: 10.1038/s41467-019-14279-8

Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study

Eric M Reiman et al. Nat Commun. 2020.

. 2020 Feb 3;11(1):667.

doi: 10.1038/s41467-019-14279-8.

Authors

Collaborators

Alzheimer’s Disease Genetics Consortium:
Erin Abner, Perrie M Adams, Marilyn S Albert, Roger L Albin, Liana G Apostolova, Steven E Arnold, Sanjay Asthana, Craig S Atwood, Clinton T Baldwin, Robert C Barber, Lisa L Barnes, Sandra Barral, James T Becker, Duane Beekly, Eileen H Bigio, Thomas D Bird, Deborah Blacker, Bradley F Boeve, James D Bowen, Adam Boxer, James R Burke, Jeffrey M Burns, Nigel J Cairns, Laura B Cantwell, Chuanhai Cao, Chris S Carlson, Cynthia M Carlsson, Regina M Carney, Minerva M Carrasquillo, Helena C Chui, David H Cribbs, Elizabeth A Crocco, Carlos Cruchaga, Charles DeCarli, Malcolm Dick, Rachelle S Doody, Ranjan Duara, Nilufer Ertekin-Taner, Denis A Evans, Kelley M Faber, Thomas J Fairchild, Kenneth B Fallon, David W Fardo, Martin R Farlow, Steven Ferris, Douglas R Galasko, Marla Gearing, Daniel H Geschwind, Valentina Ghisays, Alison M Goate, Neill R Graff-Radford, Robert C Green, John H Growdon, Hakon Hakonarson, Ronald L Hamilton, Kara L Hamilton-Nelson, Lindy E Harrell, Lawrence S Honig, Ryan M Huebinger, Christine M Hulette, Gail P Jarvik, Lee-Way Jin, Anna Karydas, Mindy J Katz, John S K Kauwe, Jeffrey A Kaye, Ronald Kim, Neil W Kowall, Joel H Kramer, Brian W Kunkle, Amanda P Kuzma, Frank M LaFerla, James J Lah, Yuk Ye Leung, James B Leverenz, Allan I Levey, Ge Li, Andrew P Lieberman, Richard B Lipton, Oscar L Lopez, Constantine G Lyketsos, John Malamon, Daniel C Marson, Eden R Martin, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Wayne C McCormick, Susan M McCurry, Andrew N McDavid, Stefan McDonough, Ann C McKee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, John C Morris, Shubhabrata Mukherjee, Adam C Naj, Sid O'Bryant, John M Olichney, Joseph E Parisi, Henry L Paulson, Elaine Peskind, Ronald C Petersen, Aimee Pierce, Wayne W Poon, Huntington Potter, Liming Qu, Joseph F Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Joan S Reisch, Christiane Reitz, John M Ringman, Erik D Roberson, Ekaterina Rogaeva, Howard J Rosen, Roger N Rosenberg, Donald R Royall, Mark A Sager, Mary Sano, Andrew J Saykin, Lon S Schneider, William W Seeley, Amanda G Smith, Joshua A Sonnen, Salvatore Spina, Peter St George-Hyslop, Robert A Stern, Russell H Swerdlow, Rudolph E Tanzi, Juan C Troncoso, Debby W Tsuang, Otto Valladares, Vivianna M Van Deerlin, Linda J Van Eldik, Badri N Vardarajan, Harry V Vinters, Sandra Weintraub, Kathleen A Welsh-Bohmer, Kirk C Wilhelmsen, Jennifer Williamson, Thomas S Wingo, Randall L Woltjer, Clinton B Wright, Chuang-Kuo Wu, Chang-En Yu, Lei Yu, Yi Zhao

Affiliations

¹ Banner Alzheimer's Institute and Arizona Alzheimer's Consortium, 901 E Willetta Street, Phoenix, AZ, 85006, USA. eric.reiman@bannerhealth.com.
² University of Arizona, 714 E Van Buren Street, Phoenix, AZ, 85006, USA. eric.reiman@bannerhealth.com.
³ Arizona State University, 522 N Central Avenue, Phoenix, AZ, 85004, USA. eric.reiman@bannerhealth.com.
⁴ Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, 445 N Fifth Street, Phoenix, AZ, 85004, USA. eric.reiman@bannerhealth.com.
⁵ Schepens Eye Research Institute of Mass Eye and Ear and the Department of Ophthalmology at Harvard Medical School, 20 Staniford Street, Boston, MA, 02114, USA.
⁶ Departments of Psychiatry and Neurology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
⁷ Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, 445 N Fifth Street, Phoenix, AZ, 85004, USA.
⁸ Banner Alzheimer's Institute and Arizona Alzheimer's Consortium, 901 E Willetta Street, Phoenix, AZ, 85006, USA.
⁹ Mayo Clinic, 13400 E Shea Boulevard, Scottsdale, AZ, 85259, USA.
¹⁰ Department of Psychiatry and Behavioral Science, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL, 33136, USA.
¹¹ Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
¹² New York Brain Bank and Department of Pathology, New York-Presbyterian Hospital at Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
¹³ Departments of Neuroscience and Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
¹⁴ Departments of Neurological Sciences and Pathology (Neuropathology), and Rush Alzheimer's Disease Center, Rush University Medical Center, 1725 W Harrison Street, Chicago, IL, 60612, USA.
¹⁵ Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, 710 West 168th Street, New York, NY, 10032, USA.
¹⁶ Kaiser Permanente Washington Health Research Institute, 1730 Minor Avenue, Seattle, WA, 98101, USA.
¹⁷ Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98198, USA.
¹⁸ Department of Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98198, USA.
¹⁹ Department of Human Genetics, Alzheimer's Disease Research Center, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.
²⁰ Department of Pathology (Neuropathology), University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.
²¹ Department of Neurology, University of Miami, 1120 NW 14th Street, Miami, FL, 33136, USA.
²² John P. Hussman Institute for Human Genomics, Department of Human Genetics, and Dr. John T. Macdonald Foundation, University of Miami, 1501 NW 10th Avenue, Miami, FL, 33136, USA.
²³ Department of Psychiatry, Vanderbilt University, 1601 23rd Avenue South, Nashville, TN, 37212, USA.
²⁴ Departments of Psychiatry, Neuroscience and Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1468 Madison Avenue, New York, NY, 10029, USA.
²⁵ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
²⁶ C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA, 02129, USA.
²⁷ Department of Pathology and Laboratory Medicine, Indiana University, 340 West 10th Street, Indianapolis, IN, 46202, USA.
²⁸ Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA, 02118, USA.
²⁹ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, PA, 19104, USA.
³⁰ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
³¹ Department of Epidemiology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
³² Department of Medical and Molecular Genetics, Indiana University, 410W 10th Street, Indianapolis, IN, 46202, USA.
³³ Institute for Computational Biology and Department of Population and Quantitative Health Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
³⁴ Taub Institute on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center Department of Neurology, Columbia University, 710 West 168th Street, New York, NY, 10032, USA.
³⁵ Biomedical Genetics Section, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
³⁶ Department of Neurology, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
³⁷ Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, Boston, MA, 02118, USA.
³⁸ Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305, USA.

PMID: 32015339
PMCID: PMC6997393
DOI: 10.1038/s41467-019-14279-8

Abstract

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.

PubMed Disclaimer

Conflict of interest statement

E.B.L. receives royalties from UpToDate, and the other authors declare no competing interests.

Figures

**Fig. 1. Percent free from Alzheimer’s dementia.**
Kaplan–Meier curves were generated from Alzheimer’s dementia cases and cognitively unimpaired non-AD controls in the neuropathologically confirmed group. Y-axis represents the percentage of persons with each APOE genotype in the neuropathologically confirmed group who remained free from Alzheimer’s dementia. X-axis denotes age at death for controls and age at onset of cases, while replacing with age at death when age at onset was unavailable.

See this image and copyright information in PMC

References

1. Coon KD, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. J. Clin. Psychiatry. 2007;68:613–618. doi: 10.4088/JCP.v68n0419. - DOI - PubMed
1. Corder EH, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 1994;7:180–184. doi: 10.1038/ng0694-180. - DOI - PubMed
1. Corder EH, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–923. doi: 10.1126/science.8346443. - DOI - PubMed
1. Farrer LA, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. Jama. 1997;278:1349–1356. doi: 10.1001/jama.1997.03550160069041. - DOI - PubMed
1. Arboleda-Velasquez, J.F. et al. Resistance to autosomal dominant Alzheimer’s in an APOE3-Christchurch homozygote. Nat Med.25, 1680–1683 (2019). - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study

Collaborators

Affiliations

Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous